tbuckley/cabot-search huggingface dataset:
International Consensus on Differential Diagnosis and Management of Patients With Danon Disease
Authors: Kimberly N. Hong, Emily A. Eshraghian, Michael Arad, Alessia Argirò, Michela Brambatti, Quan Bui, Oren Caspi, Fernando de Frutos, Barry Greenberg, Carolyn Y. Ho, Juan Pablo Kaski, Iacopo Olivotto, Matthew R.G. Taylor, Abigail Yesso, Pablo Garcia-Pavia, Eric D. Adler
Journal: Journal of the American College of Cardiology (2023)

Danon disease is a rare X-linked autophagic vacuolar cardioskeletal myopathy associated with severe heart failure that can be accompanied with extracardiac neurologic, skeletal, and ophthalmologic manifestations. It is caused by loss of function variants in the LAMP2 gene and is among the most severe and penetrant of the genetic cardiomyopathies. Most patients with Danon disease will experience symptomatic heart failure. Male individuals generally present earlier than women and die of either heart failure or arrhythmia or receive a heart transplant by the third decade of life. Herein, the authors review the differential diagnosis of Danon disease, diagnostic criteria, natural history, management recommendations, and recent advances in treatment of this increasingly recognized and extremely morbid cardiomyopathy.
Comparison of Antiplatelet Monotherapies After Percutaneous Coronary Intervention According to Clinical, Ischemic, and Bleeding Risks
Authors: Seokhun Yang, Jeehoon Kang, Kyung Woo Park, Seung-Ho Hur, Nam Ho Lee, Doyeon Hwang, Han-Mo Yang, Hyo-Suk Ahn, Kwang Soo Cha, Sang-Ho Jo, Jae Kean Ryu, Il-Woo Suh, Hyun-Hee Choi, Seong-Ill Woo, Jung-Kyu Han, Eun-Seok Shin, Bon-Kwon Koo, Hyo-Soo Kim
Journal: Journal of the American College of Cardiology (2023)
Non-linear association of baseline viral load with on-treatment hepatocellular carcinoma risk in chronic hepatitis B
Authors: Won-Mook Choi, Gi-Ae Kim, Jonggi Choi, Gwang Hyeon Choi, Yun Bin Lee, Dong Hyun Sinn, Young-Suk Lim
Journal: Gut (2023)

Objective The association between baseline pretreatment serum HBV DNA levels and on-treatment hepatocellular carcinoma (HCC) risk remains controversial in patients with chronic hepatitis B (CHB). We aimed to investigate the association between baseline HBV viral load and on-treatment HCC risk in CHB patients without cirrhosis. Design Using a multicentre historical cohort study including 4693 hepatitis B e antigen (HBeAg)-negative and HBeAg-positive, adult CHB patients without cirrhosis who initiated antiviral treatment, HCC risk was estimated by baseline HBV viral load as a categorical variable. Results During a median of 7.6 years of antiviral treatment, 193 patients developed HCC (0.53 per 100 person- years). Baseline HBV DNA level was independently associated with on-treatment HCC risk in a non-linear, parabolic pattern. Patients with moderate baseline viral loads (5.00–7.99 log 10 IU/mL) exhibited the highest HCC risk (HR, 2.60; p&lt;0.001), followed by those with low viral loads (3.30–4.99 log 10 IU/mL; HR, 1.66; p=0.11). Patients with high viral loads (≥8.00 log 10 IU/mL) presented the lowest HCC risk. Particularly, patients with baseline HBV DNA levels 6.00–6.99 log 10 IU/mL had the highest on-treatment HCC risk (HR, 3.36; p&lt;0.001) compared with those with baseline HBV DNA levels≥8.00 log 10 IU/mL. These findings were more prominent among HBeAg-positive patients, younger patients, or those with less advanced hepatic fibrosis. Conclusion Patients with moderate baseline viral load, particularly around 6 log 10 IU/mL, demonstrated the highest on-treatment HCC risk, despite long-term antiviral treatment. Early initiation of antiviral treatment, tailored to viral load, should be considered to minimise HCC risk in adult CHB patients without cirrhosis.
Identification of molecular subphenotypes in two cohorts of paediatric ARDS
Authors: Nadir Yehya, Matt S Zinter, Jill M Thompson, Michelle J Lim, Mark R Hanudel, Mustafa F Alkhouli, Hector Wong, Matthew N Alder, Daniel J McKeone, E Scott Halstead, Pratik Sinha, Anil Sapru
Journal: Thorax (2023)

Two subphenotypes of acute respiratory distress syndrome (ARDS), hypoinflammatory and hyperinflammatory, have been reported in adults and in a single paediatric cohort. The relevance of these subphenotypes in paediatrics requires further investigation. We aimed to identify subphenotypes in two large observational cohorts of paediatric ARDS and assess their congruence with prior descriptions.
Card9/neutrophil signalling axis promotes IL-17A-mediated ankylosing spondylitis
Authors: Holly L Rosenzweig, Emily E Vance, Kofi Asare-Konadu, Kylie V Koney, Ellen J Lee, Atul A Deodhar, Rouhin Sen, Liron Caplan, Ruth J Napier
Journal: Annals of the Rheumatic Diseases (2023)

Objective Polymorphisms in the antifungal signalling molecule CARD9 are associated with ankylosing spondylitis (AS). Here, we investigated the cellular mechanism by which CARD9 controls pathogenic Th17 responses and the onset of disease in both experimental murine AS and patients. Methods Experiments in SKG, Card9 −/− SKG, neutrophil-deplete SKG mice along with in vitro murine, neutrophil and CD4 + T cell cocultures examined Card9 function in neutrophil activation, Th17 induction and arthritis in experimental AS. In AS patients the neutrophil: Bath Ankylosing Spondylitis Functional Index relationship was analysed. In vitro studies with autologous neutrophil: T cell cocultures examined endogenous CARD9 versus the AS-associated variant (rs4075515) of CARD9 in T cellular production of IL-17A. Results Card9 functioned downstream of Dectin-1 and was essential for induction of Th17 cells, arthritis and spondylitis in SKG mice. Card9 expression within T cells was dispensable for arthritis onset in SKG mice. Rather, Card9 expression controlled neutrophil function; and neutrophils in turn, were responsible for triggering Th17 expansion and disease in SKG mice. Mechanistically, cocultures of zymosan prestimulated neutrophils and SKG T cells revealed a direct cellular function for Card9 within neutrophils in the potentiation of IL-17 production by CD4 + T cells on TCR-ligation. The clinical relevance of the neutrophil-Card9-coupled mechanism in Th17-mediated disease is supported by a similar observation in AS patients. Neutrophils from HLA-B27 + AS patients expanded autologous Th17 cells in vitro , and the AS-associated CARD9 S12N variant increased IL-17A. Conclusions These data reveal a novel neutrophil-intrinsic role for Card9 in arthritogenic Th17 responses and AS pathogenesis. These data provide valuable utility in our future understanding of CARD9-specific mechanisms in spondyloarthritis .
Exploring the healthcare experiences and support needs of chestfeeding or breastfeeding for trans and non-binary parents based in the United Kingdom
Authors: Jessica Eve Jackson, Ray Wild, Jenny Hallam, Rudy Graves, B. J. Woodstein, Penny Stothard
Journal: International Journal of Transgender Health (2023)

Trans and/or non-binary parents experience structural exclusion in family healthcare and there is a need for specialist training for healthcare professionals so that they are able to create a gender inclusive environment.
Glutamine mimicry suppresses tumor progression through asparagine metabolism in pancreatic ductal adenocarcinoma
Authors: Maria Victoria Recouvreux, Shea F. Grenier, Yijuan Zhang, Edgar Esparza, Guillem Lambies, Cheska Marie Galapate, Swetha Maganti, Karen Duong-Polk, Deepika Bhullar, Razia Naeem, David A. Scott, Andrew M. Lowy, Hervé Tiriac, Cosimo Commisso
Journal: Nature Cancer (2023)
Targeting pancreatic cancer metabolic dependencies through glutamine antagonism
Authors: Joel Encarnación-Rosado, Albert S. W. Sohn, Douglas E. Biancur, Elaine Y. Lin, Victoria Osorio-Vasquez, Tori Rodrick, Diana González-Baerga, Ende Zhao, Yumi Yokoyama, Diane M. Simeone, Drew R. Jones, Seth J. Parker, Robert Wild, Alec C. Kimmelman
Journal: Nature Cancer (2023)

Abstract Pancreatic ductal adenocarcinoma (PDAC) cells use glutamine (Gln) to support proliferation and redox balance. Early attempts to inhibit Gln metabolism using glutaminase inhibitors resulted in rapid metabolic reprogramming and therapeutic resistance. Here, we demonstrated that treating PDAC cells with a Gln antagonist, 6-diazo-5-oxo- l -norleucine (DON), led to a metabolic crisis in vitro. In addition, we observed a profound decrease in tumor growth in several in vivo models using sirpiglenastat (DRP-104), a pro-drug version of DON that was designed to circumvent DON-associated toxicity. We found that extracellular signal-regulated kinase (ERK) signaling is increased as a compensatory mechanism. Combinatorial treatment with DRP-104 and trametinib led to a significant increase in survival in a syngeneic model of PDAC. These proof-of-concept studies suggested that broadly targeting Gln metabolism could provide a therapeutic avenue for PDAC. The combination with an ERK signaling pathway inhibitor could further improve the therapeutic outcome.
Activity map of a cortico-cerebellar loop underlying motor planning
Authors: Jia Zhu, Hana Hasanbegović, Liu D. Liu, Zhenyu Gao, Nuo Li
Journal: Nature Neuroscience (2023)

The neocortex and cerebellum interact to mediate cognitive functions. It remains unknown how the two structures organize into functional networks to mediate specific behaviors. Here we delineate activity supporting motor planning in relation to the mesoscale cortico-cerebellar connectome. In mice planning directional licking based on short-term memory, preparatory activity instructing future movement depends on the anterior lateral motor cortex (ALM) and the cerebellum. Transneuronal tracing revealed divergent and largely open-loop connectivity between the ALM and distributed regions of the cerebellum. A cerebellum-wide survey of neuronal activity revealed enriched preparatory activity in hotspot regions with conjunctive input-output connectivity to the ALM. Perturbation experiments show that the conjunction regions were required for maintaining preparatory activity and correct subsequent movement. Other cerebellar regions contributed little to motor planning despite input or output connectivity to the ALM. These results identify a functional cortico-cerebellar loop and suggest the cerebellar cortex selectively establishes reciprocal cortico-cerebellar communications to orchestrate motor planning.
Rapid discovery of high-affinity antibodies via massively parallel sequencing, ribosome display and affinity screening
Authors: Benjamin T. Porebski, Matthew Balmforth, Gareth Browne, Aidan Riley, Kiarash Jamali, Maximillian J. L. J. Fürst, Mirko Velic, Andrew Buchanan, Ralph Minter, Tristan Vaughan, Philipp Holliger
Journal: Nature Biomedical Engineering (2023)

Abstract Developing therapeutic antibodies is laborious and costly. Here we report a method for antibody discovery that leverages the Illumina HiSeq platform to, within 3 days, screen in the order of 10 8 antibody–antigen interactions. The method, which we named ‘deep screening’, involves the clustering and sequencing of antibody libraries, the conversion of the DNA clusters into complementary RNA clusters covalently linked to the instrument’s flow-cell surface on the same location, the in situ translation of the clusters into antibodies tethered via ribosome display, and their screening via fluorescently labelled antigens. By using deep screening, we discovered low-nanomolar nanobodies to a model antigen using 4 × 10 6 unique variants from yeast-display-enriched libraries, and high-picomolar single-chain antibody fragment leads for human interleukin-7 directly from unselected synthetic repertoires. We also leveraged deep screening of a library of 2.4 × 10 5 sequences of the third complementarity-determining region of the heavy chain of an anti-human epidermal growth factor receptor 2 (HER2) antibody as input for a large language model that generated new single-chain antibody fragment sequences with higher affinity for HER2 than those in the original library.
Subretinal timrepigene emparvovec in adult men with choroideremia: a randomized phase 3 trial
Authors: Robert E. MacLaren, M. Dominik Fischer, James A. Gow, Byron L. Lam, Eeva-Marja K. Sankila, Aniz Girach, Sushil Panda, Dan Yoon, Guolin Zhao, Mark E. Pennesi
Journal: Nature Medicine (2023)

Choroideremia is a rare, X-linked retinal degeneration resulting in progressive vision loss. A randomized, masked, phase 3 clinical trial evaluated the safety and efficacy over 12 months of follow-up in adult males with choroideremia randomized to receive a high-dose (1.0 × 1011 vector genomes (vg); n = 69) or low-dose (1.0 × 1010 vg; n = 34) subretinal injection of the AAV2-vector-based gene therapy timrepigene emparvovec versus non-treated control (n = 66). Most treatment-emergent adverse events were mild or moderate. The trial did not meet its primary endpoint of best-corrected visual acuity (BCVA) improvement. In the primary endpoint analysis, three of 65 participants (5%) in the high-dose group, one of 34 (3%) participants in the low-dose group and zero of 62 (0%) participants in the control group had ≥15-letter Early Treatment Diabetic Retinopathy Study (ETDRS) improvement from baseline BCVA at 12 months (high dose, P = 0.245 versus control; low dose, P = 0.354 versus control). As the primary endpoint was not met, key secondary endpoints were not tested for significance. In a key secondary endpoint, nine of 65 (14%), six of 35 (18%) and one of 62 (2%) participants in the high-dose, low-dose and control groups, respectively, experienced ≥10-letter ETDRS improvement from baseline BCVA at 12 months. Potential opportunities to enhance future gene therapy studies for choroideremia include optimization of entry criteria (more preserved retinal area), surgical techniques and clinical endpoints. EudraCT registration: 2015-003958-41 .
The malate shuttle detoxifies ammonia in exhausted T cells by producing 2-ketoglutarate
Authors: Nina Weisshaar, Sicong Ma, Yanan Ming, Alaa Madi, Alessa Mieg, Marvin Hering, Ferdinand Zettl, Kerstin Mohr, Nora Ten Bosch, Diana Stichling, Michael Buettner, Gernot Poschet, Glynis Klinke, Michael Schulz, Nina Kunze-Rohrbach, Carolin Kerber, Isabel Madeleine Klein, Jingxia Wu, Xi Wang, Guoliang Cui
Journal: Nature Immunology (2023)

Abstract The malate shuttle is traditionally understood to maintain NAD + /NADH balance between the cytosol and mitochondria. Whether the malate shuttle has additional functions is unclear. Here we show that chronic viral infections induce CD8 + T cell expression of GOT1, a central enzyme in the malate shuttle. Got1 deficiency decreased the NAD + /NADH ratio and limited antiviral CD8 + T cell responses to chronic infection; however, increasing the NAD + /NADH ratio did not restore T cell responses. Got1 deficiency reduced the production of the ammonia scavenger 2-ketoglutarate (2-KG) from glutaminolysis and led to a toxic accumulation of ammonia in CD8 + T cells. Supplementation with 2-KG assimilated and detoxified ammonia in Got1 -deficient T cells and restored antiviral responses. These data indicate that the major function of the malate shuttle in CD8 + T cells is not to maintain the NAD + /NADH balance but rather to detoxify ammonia and enable sustainable ammonia-neutral glutamine catabolism in CD8 + T cells during chronic infection.
ctDNA response after pembrolizumab in non-small cell lung cancer: phase 2 adaptive trial results
Authors: Valsamo Anagnostou, Cheryl Ho, Garth Nicholas, Rosalyn Anne Juergens, Adrian Sacher, Andrea S. Fung, Paul Wheatley-Price, Scott A. Laurie, Benjamin Levy, Julie R. Brahmer, Archana Balan, Noushin Niknafs, Egor Avrutin, Liting Zhu, Mark Sausen, Penelope A. Bradbury, Jill O’Donnell-Tormey, Pierre Olivier Gaudreau, Keyue Ding, Janet Dancey
Journal: Nature Medicine (2023)

Circulating tumor DNA (ctDNA) has shown promise in capturing primary resistance to immunotherapy. BR.36 is a multi-center, randomized, ctDNA-directed, phase 2 trial of molecular response-adaptive immuno-chemotherapy for patients with lung cancer. In the first of two independent stages, 50 patients with advanced non-small cell lung cancer received pembrolizumab as standard of care. The primary objectives of stage 1 were to ascertain ctDNA response and determine optimal timing and concordance with radiologic Response Evaluation Criteria in Solid Tumors (RECIST) response. Secondary endpoints included the evaluation of time to ctDNA response and correlation with progression-free and overall survival. Maximal mutant allele fraction clearance at the third cycle of pembrolizumab signified molecular response (mR). The trial met its primary endpoint, with a sensitivity of ctDNA response for RECIST response of 82% (90% confidence interval (CI): 52-97%) and a specificity of 75% (90% CI: 56.5-88.5%). Median time to ctDNA response was 2.1 months (90% CI: 1.5-2.6), and patients with mR attained longer progression-free survival (5.03 months versus 2.6 months) and overall survival (not reached versus 7.23 months). These findings are incorporated into the ctDNA-driven interventional molecular response-adaptive second stage of the BR.36 trial in which patients at risk of progression are randomized to treatment intensification or continuation of therapy. ClinicalTrials.gov ID: NCT04093167 .
Age-dependent topic modeling of comorbidities in UK Biobank identifies disease subtypes with differential genetic risk
Authors: Xilin Jiang, Martin Jinye Zhang, Yidong Zhang, Arun Durvasula, Michael Inouye, Chris Holmes, Alkes L. Price, Gil McVean
Journal: Nature Genetics (2023)

Abstract The analysis of longitudinal data from electronic health records (EHRs) has the potential to improve clinical diagnoses and enable personalized medicine, motivating efforts to identify disease subtypes from patient comorbidity information. Here we introduce an age-dependent topic modeling (ATM) method that provides a low-rank representation of longitudinal records of hundreds of distinct diseases in large EHR datasets. We applied ATM to 282,957 UK Biobank samples, identifying 52 diseases with heterogeneous comorbidity profiles; analyses of 211,908 All of Us samples produced concordant results. We defined subtypes of the 52 heterogeneous diseases based on their comorbidity profiles and compared genetic risk across disease subtypes using polygenic risk scores (PRSs), identifying 18 disease subtypes whose PRS differed significantly from other subtypes of the same disease. We further identified specific genetic variants with subtype-dependent effects on disease risk. In conclusion, ATM identifies disease subtypes with differential genome-wide and locus-specific genetic risk profiles.
The ligation between ERMAP, galectin-9 and dectin-2 promotes Kupffer cell phagocytosis and antitumor immunity
Authors: Jie Li, Xiao-gang Liu, Rui-liang Ge, Yu-peng Yin, Yong-da Liu, Wan-peng Lu, Mei Huang, Xue-ying He, Jinghan Wang, Guoxiang Cai, Shu-han Sun, Ji-hang Yuan
Journal: Nature Immunology (2023)
Microglia and complement mediate early corticostriatal synapse loss and cognitive dysfunction in Huntington’s disease
Authors: Daniel K. Wilton, Kevin Mastro, Molly D. Heller, Frederick W. Gergits, Carly Rose Willing, Jaclyn B. Fahey, Arnaud Frouin, Anthony Daggett, Xiaofeng Gu, Yejin A. Kim, Richard L. M. Faull, Suman Jayadev, Ted Yednock, X. William Yang, Beth Stevens
Journal: Nature Medicine (2023)

Abstract Huntington’s disease (HD) is a devastating monogenic neurodegenerative disease characterized by early, selective pathology in the basal ganglia despite the ubiquitous expression of mutant huntingtin. The molecular mechanisms underlying this region-specific neuronal degeneration and how these relate to the development of early cognitive phenotypes are poorly understood. Here we show that there is selective loss of synaptic connections between the cortex and striatum in postmortem tissue from patients with HD that is associated with the increased activation and localization of complement proteins, innate immune molecules, to these synaptic elements. We also found that levels of these secreted innate immune molecules are elevated in the cerebrospinal fluid of premanifest HD patients and correlate with established measures of disease burden. In preclinical genetic models of HD, we show that complement proteins mediate the selective elimination of corticostriatal synapses at an early stage in disease pathogenesis, marking them for removal by microglia, the brain’s resident macrophage population. This process requires mutant huntingtin to be expressed in both cortical and striatal neurons. Inhibition of this complement-dependent elimination mechanism through administration of a therapeutically relevant C1q function-blocking antibody or genetic ablation of a complement receptor on microglia prevented synapse loss, increased excitatory input to the striatum and rescued the early development of visual discrimination learning and cognitive flexibility deficits in these models. Together, our findings implicate microglia and the complement cascade in the selective, early degeneration of corticostriatal synapses and the development of cognitive deficits in presymptomatic HD; they also provide new preclinical data to support complement as a therapeutic target for early intervention.
COX17 acetylation via MOF–KANSL complex promotes mitochondrial integrity and function
Authors: Sukanya Guhathakurta, Niyazi Umut Erdogdu, Juliane J. Hoffmann, Iga Grzadzielewska, Alexander Schendzielorz, Janine Seyfferth, Christoph U. Mårtensson, Mauro Corrado, Adam Karoutas, Bettina Warscheid, Nikolaus Pfanner, Thomas Becker, Asifa Akhtar
Journal: Nature Metabolism (2023)

Abstract Reversible acetylation of mitochondrial proteins is a regulatory mechanism central to adaptive metabolic responses. Yet, how such functionally relevant protein acetylation is achieved remains unexplored. Here we reveal an unprecedented role of the MYST family lysine acetyltransferase MOF in energy metabolism via mitochondrial protein acetylation. Loss of MOF–KANSL complex members leads to mitochondrial defects including fragmentation, reduced cristae density and impaired mitochondrial electron transport chain complex IV integrity in primary mouse embryonic fibroblasts. We demonstrate COX17, a complex IV assembly factor, as a bona fide acetylation target of MOF. Loss of COX17 or expression of its non-acetylatable mutant phenocopies the mitochondrial defects observed upon MOF depletion. The acetylation-mimetic COX17 rescues these defects and maintains complex IV activity even in the absence of MOF, suggesting an activatory role of mitochondrial electron transport chain protein acetylation. Fibroblasts from patients with MOF syndrome who have intellectual disability also revealed respiratory defects that could be restored by alternative oxidase, acetylation-mimetic COX17 or mitochondrially targeted MOF. Overall, our findings highlight the critical role of MOF–KANSL complex in mitochondrial physiology and provide new insights into MOF syndrome.